Autotaxin (ATX) is a member of the nucleotide pyrophosphate (NPP) family of enzymes. ATX is also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (NPP2). ATX catalyzes the hydrolysis of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA).
ATX is required for normal development. As reported in Tanaka et al, J. Biol. Chem., 281 (35):25822-25830 (2006); and van Meeteren et al, Mol. Cell Biol., 26 (13):5015-5022 (2006), homozygous ATX knockout mice die in utero at day 9.5, coinciding with a period of vascular stabilization. As reported in Fotopoulou et al, Dev. Biol. 2010, 339 (2):451-464 (2010), ATX also is important in development of the nervous system as ATX knockout mice show defects in neural tube development.
LPA is a signaling molecule that acts as a potent mitogen by activating G-protein coupled receptors. LPA is also a mitogen and an anti-apoptotic agent, which provides survival advantages to carcinomas that utilize LPA. Certain cancers, such as ovarian cancers, produce high levels of LPA.
ATX is one of the most upregulated genes in highly metastatic cancers, as reported in Luer et al, Anticancer Res., 22 (2A):733-740 (2002). Liu et al, Cancer Cell, 15 (6):539-550 (2009) reported that ectopic expression of ATX in mice leads to mammary intraepithelial neoplasia, which develops into invasive and metastatic tumors. Samadi et al, Oncogene. 28 (7):1028-1039 (2009) reported that ATX inhibits paclitaxel-induced apoptosis in breast cancer cells, and E et al, J. Biol. Chem., 284 (21):14558-14571 (2009) reported that LPA renders ovarian cancer cells chemoresistant to cisplatin and adriamycin. Jazaeti et al, Clin. Cancer Res., 11 (17):6300-6310 (2005) reported that ATX is also overexpressed in patients with recurrent disease after prior treatment with chemotherapy. In a genome-wide siRNA screen, Vidot et al, Cell Signal., 22 (6):926-935 (2010) identified ATX as a candidate drug-resistance gene in ovarian cancer.
The ATX-LPC-LPA receptor axis is a promising therapeutic target for the management of cancer metastasis and therapeutic resistance. As reported in Tsuda et al, J. Biol. Chem., 281 (36):26081-26088 (2006); and van Meeteren et al, J. Biol. Chem., 280 (22):21155-21161 (2005), ATX shows feedback inhibition by its hydrolysis products LPA, CPA, and sphingosine-1-phosphate (S1P). Thus, many initially identified ATX inhibitors are lipid-like substrate or product analogs, as reported in Durgarn et al, Bioorg. Med. Chem. Lett., 16 (3):633-640 (2006); Albers et al, J. Med. Chem., 53 (13):4958-4967 (2010); Albers et al. Proc. Natl. Acad. Sci., 107 (16):7257-7262 (2010); Baker et al, J. Biol. Chem., 281 (32):22786-22793 (2006); Gajewiak et al, Org. Lett., 10 (6):1111-1114 (2008); Gajewiak et al, Chem. Med. Chem., 2 (12):1789-1798 (2007); Zhang, et al, Cancer Res., 69 (13):5441-5449 (2009); and Uchiyama et al, Biochim. Biophys, Acta, 1771 (1):103-112 (2007). However, the characteristics of such lipid-like compounds limit their utility as potential lead compounds for drug development.
Recently, Ferry et al, J. Pharmacol. Exp. Ther., 327 (3):809-819 (2008), described a non-lipid ATX inhibitor 4-tetradecanoylaminobenzyl phosphonic acid (S32826) that possessed nanomolar activity in-vitro. Unfortunately, S32826 failed to show activity in cellular and in-vivo systems. Hydrolysis of the amide bond present in S32826 could be the reason for its instability and thus lack of activity in cellular systems. The structure of S32826 is shown below as Formula A.

Thus, a significant need exists for a chemical compound that is an inhibitor of ATX and that is active in cellular systems.
The following abbreviations are used in the figures and in the following description of the invention:
Pd(OAC)2=Palladium (II) acetate; Et3N=Triethyl amine; DMF=Dimethyl formamide; LAH=Lithium aluminum hydride; THF=Tetrahydrofuran; PBr3=Phosphorous tribromide; P(OMe)3=Trimethyl phosphate; PDC=Pyridinium dichromate; TMSBr=Timethylsilyl bromide; DAST=Diethylaminosulfur trifluoride; CH3CN=Acetonitrile; MeOH=Methanol; H2O2=Hydrogen peroxide; DCM=Dichloromethane; EtOAc=Ethyl acetate; DMSO=Dimethyl sulfoxide; KOH=Potassium hydroxide; K2CO3=Potassium carbonate; MgSO4=Magnesium sulfate; HCl=Hydrochloric acid; SOCl2=Thionyl chloride; RT=Room temperature; Equiv=Equivalent; ATX=Autotaxin; LPC=Lysophosphatidylcholine; LPLD=Lysophospholipase D; LPA=Lysophosphatidic acid; CPA=Cyclophosphatidic acid; S1P=Sphingosine-1-phosphate; LPAR=Lysophosphatidic acid receptors; LPA-BP=LPA bromophosphonate; HUVEC=Human umbilical cord vascular endothelial cell; NMR=Nuclear Magnetic resonance; ESI=Electrospray/ion; HRMS=High-resolution mass; TLC=Thin-layer chromatography